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Common genetic variation in obesity, lipid transfer genes and risk of Metabolic Syndrome: Results from IDEFICS/I.Family study and meta-analysis.
Nagrani, R, Foraita, R, Gianfagna, F, Iacoviello, L, Marild, S, Michels, N, Molnár, D, Moreno, L, Russo, P, Veidebaum, T, et al
Scientific reports. 2020;(1):7189
Abstract
As the prevalence of metabolic syndrome (MetS) in children and young adults is increasing, a better understanding of genetics that underlie MetS will provide critical insights into the origin of the disease. We examined associations of common genetic variants and repeated MetS score from early childhood to adolescence in a pan-European, prospective IDEFICS/I.Family cohort study with baseline survey and follow-up examinations after two and six years. We tested associations in 3067 children using a linear mixed model and confirmed the results with meta-analysis of identified SNPs. With a stringent Bonferroni adjustment for multiple comparisons we obtained significant associations(p < 1.4 × 10-4) for 5 SNPs, which were in high LD (r2 > 0.85) in the 16q12.2 non-coding intronic chromosomal region of FTO gene with strongest association observed for rs8050136 (effect size(β) = 0.31, pWald = 1.52 × 10-5). We also observed a strong association of rs708272 in CETP with increased HDL (p = 5.63 × 10-40) and decreased TRG (p = 9.60 × 10-5) levels. These findings along with meta-analysis advance etiologic understanding of childhood MetS, highlighting that genetic predisposition to MetS is largely driven by genes of obesity and lipid metabolism. Inclusion of the associated genetic variants in polygenic scores for MetS may prove to be fundamental for identifying children and subsequently adults of the high-risk group to allow earlier targeted interventions.
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Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk.
Masson, W, Lobo, M, Siniawski, D, Huerín, M, Molinero, G, Valéro, R, Nogueira, JP
Diabetes & metabolism. 2018;(6):508-513
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BACKGROUND Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. METHODS A meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. RESULTS Four eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81-0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=-1.13, P=0.26). CONCLUSION CETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration.
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Effect of Cholesteryl Ester Transfer Protein Gene TaqIB Polymorphism on the Risk of Ischemic Stroke: A Meta-Analysis.
Yu, DD, Ren, QQ, Dong, B, Zhao, DD, Sun, YH
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2017;(10):2354-2361
Abstract
BACKGROUND The association between cholesteryl ester transfer protein (CETP) TaqIB polymorphism and ischemic stroke (IS) risk has generated conflicting results. To investigate whether the TaqIB polymorphism of the CETP gene was associated with the risk of IS, a meta-analysis was performed. METHODS Studies were retrieved by searching PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Wanfang Database, and the Chinese VIP Database before January 16, 2017. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association. Depending on the heterogeneity the fixed-effects model or the random-effects model was used. RESULTS A total of 6 case-control studies were identified with 1494 cases and 1370 controls. Overall, an association of CETP TaqIB polymorphism with IS was found in the 4 genetic models (B2B2 versus B1B1: OR = .63, 95% CI = .51-.79, P < .001; B1B2 + B2B2 versus B1B1: OR = .75, 95% CI = .64-.87, P < .001; B2B2 versus B1B2 + B1B1: OR = .70, 95% CI = .57-.85, P < .001; B2 versus B1: OR = .78, 95% CI = .70-.87, P < .001). In the subgroup analysis by ethnicity, similar risks were also observed in Asian population. CONCLUSIONS This meta-analysis indicates that CETP TaqIB polymorphism is associated with IS risk, and the B2 allele is a protective factor for IS.
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A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.
Lin, S, Dai, R, Lin, R
Oncotarget. 2017;(2):2153-2163
Abstract
Lipid metabolism plays an essential role in the pathogenesis of atherosclerosis, a major cause for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) is an important glycoprotein involved in lipid metabolism by transferring cholesteryl esters to apolipoprotein B-containing lipoproteins in exchange for triglycerides. The objective of this meta-analysis was to evaluate the association of CETP C-629A polymorphism with CHD risk and lipid changes. Four public databases were searched, and data from 17 qualified articles were extracted in duplicate and analyzed by STATA software. Overall association of C-629A with CHD risk was nonsignificant in 5441 patients and 7967 controls. Subgroup analyses by ethnicity revealed significance only in Caucasians, with the odds of CHD being 1.18, 1.43 and 1.41 under allelic, genotypic and dominant models, respectively (P < 0.001). Similarly, the -629C allele increased the corresponding risk of myocardial infarction by 1.23-, 1.28- and 1.29-fold (P < 0.02). The association of C-629A with CHD was significantly strengthened in prospective and large studies. Moreover, carriers of the -629C allele had significant higher levels of circulating CETP (weighted mean difference [WMD]: 0.45 μg/mL; 95% confidence interval [CI]: 0.25 to 0.65; P < 0.001), but lower levels of high-density lipoprotein cholesterol (HDL-C) (WMD: -3.65 mg/dL; 95% CI: -5.59 to -1.70; P < 0.001) relative to the -629AA homozygotes. The probability of publication bias was low. Our meta-analytic findings collectively demonstrate that the -629C allele was significantly associated with an increased risk of CHD in Caucasians, and this association may be mediated by its phenotypic regulation on circulating CETP and HDL-C.
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Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.
Postmus, I, Warren, HR, Trompet, S, Arsenault, BJ, Avery, CL, Bis, JC, Chasman, DI, de Keyser, CE, Deshmukh, HA, Evans, DS, et al
Journal of medical genetics. 2016;(12):835-845
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BACKGROUND In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
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Effects of HDL-modifiers on cardiovascular outcomes: a meta-analysis of randomized trials.
Verdoia, M, Schaffer, A, Suryapranata, H, De Luca, G
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2015;(1):9-23
Abstract
BACKGROUND AND AIM High density lipoproteins (HDL) have been addressed as a potential strategy for cardiovascular prevention, with great controversies on pharmacological approaches for HDL-elevation. Our aim was to compare HDL-rising treatment with niacin or CETP-inhibitors with optimal medical therapy in cardiovascular outcome. METHODS AND RESULTS Randomized trials were searched. Primary endpoint was cardiovascular death, secondary were: non fatal myocardial infarction; coronary revascularization; cerebrovascular accidents and safety endpoints. As many as 18 randomized trials, for a total of 69,515 patients, were included. HDL-modifiers did not reduce cardiovascular mortality (2.3%vs3.4%; OR [95%CI] = 0.96 [0.87-1.05], p = 0.37, phet = 0.58), with no benefit from niacin/CETP inhibitors according to patients' risk profile (beta [95%CI] = -0.14 [-0.29 to 0.02], p = 0.09) or the amount of HDL increase (beta [95%CI] = 0.014 [-0.008 to 0.04], p = 0.21). Niacin but not CETP-I reduced myocardial infarction and coronary revascularization, but higher rate of SAE occurred with HDL-modifiers (OR [95%CI] = 1.24 [1.18-1.31], p < 0.00001, phet = 0.02), in particular new onset of diabetes with niacin and worsening of hypertension with CETP-inhibitors. CONCLUSIONS Niacin and CETP inhibitors do not influence cardiovascular mortality. Significant benefits in MI and coronary revascularization were observed with niacin, despite the higher occurrence of diabetes.
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Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis.
Hourcade-Potelleret, F, Laporte, S, Lehnert, V, Delmar, P, Benghozi, R, Torriani, U, Koch, R, Mismetti, P
Heart (British Cardiac Society). 2015;(11):847-53
Abstract
CONTEXT Epidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer protein (CETP) inhibitors. OBJECTIVES To assess alternative methods to predict clinical response of CETP inhibitors. METHODS Meta-regression analysis on raising HDL-C drugs (statins, fibrates, niacin) in randomised controlled trials. RESULTS 51 trials in secondary prevention with a total of 167,311 patients for a follow-up >1 year where HDL-C was measured at baseline and during treatment. The meta-regression analysis showed no significant association between change in HDL-C (treatment vs comparator) and log risk ratio (RR) of clinical endpoint (non-fatal myocardial infarction or cardiac death). CETP inhibitors data are consistent with this finding (RR: 1.03; P5-P95: 0.99-1.21). A prespecified sensitivity analysis by drug class suggested that the strength of relationship might differ between pharmacological groups. A significant association for both statins (p<0.02, log RR=-0.169-0.0499*HDL-C change, R(2)=0.21) and niacin (p=0.02, log RR=1.07-0.185*HDL-C change, R(2)=0.61) but not fibrates (p=0.18, log RR=-0.367+0.077*HDL-C change, R(2)=0.40) was shown. However, the association was no longer detectable after adjustment for low-density lipoprotein cholesterol for statins or exclusion of open trials for niacin. CONCLUSIONS Meta-regression suggested that CETP inhibitors might not influence coronary risk. The relation between change in HDL-C level and clinical endpoint may be drug dependent, which limits the use of HDL-C as a surrogate marker of coronary events. Other markers of HDL function may be more relevant.
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CETP/LPL/LIPC gene polymorphisms and susceptibility to age-related macular degeneration.
Wang, YF, Han, Y, Zhang, R, Qin, L, Wang, MX, Ma, L
Scientific reports. 2015;:15711
Abstract
Three high-density lipoprotein (HDL)-related loci have been reported to be associated with age-related macular degeneration (AMD), but the results were inconsistent. In this study, the cholesteryl ester transfer protein (CETP) rs3764261 variant was significantly associated with an increased risk of AMD (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.05-1.21, P < 0.001), and the hepatic lipase (LIPC) rs10468017 variant was associated with a significantly decreased risk of AMD (OR = 0.81, CI: 0.76-0.86, P < 0.001). Individuals carrying the lipoprotein lipase (LPL) rs12678919 polymorphism (A → G) had no significant change in the risk of developing AMD (OR = 1.01, CI: 0.92-1.10, P = 0.17). After adjusting for the complement factor H (CFH) gene, both CETP and LPL conferred a significantly increased AMD risk (ORCETP = 1.17, CI: 1.08-1.26, P < 0.001; ORLPL = 1.11, CI: 1.01-1.22, P = 0.02). Subgroup analysis based on ethnicity revealed a significant association between the CETP variant and AMD in both Americans (OR = 1.12, CI: 1.02-1.23, P = 0.01) and Europeans (OR = 1.10, CI: 1.01-1.19, P = 0.011). This meta-analysis revealed that both CETP rs3764261 and LIPC rs10468017 polymorphisms were significantly associated with AMD risk. After adjustment for the CFH gene, CETP/LPL conferred a significantly increased susceptibility to the disease, indicating potential interactions among genes in the complement system and the lipid metabolism pathway.
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Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients.
Keene, D, Price, C, Shun-Shin, MJ, Francis, DP
BMJ (Clinical research ed.). 2014;:g4379
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OBJECTIVE To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels. DESIGN Meta-analysis. STUDIES REVIEWED Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke). RESULTS 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference. CONCLUSIONS Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.
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Meta-analysis of cholesteryl ester transfer protein TaqIB polymorphism and risk of myocardial infarction.
Cao, M, Zhou, ZW, Fang, BJ, Zhao, CG, Zhou, D
Medicine. 2014;(26):e160
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A number of studies have been conducted to explore the association between the cholesteryl ester transfer protein (CETP) TaqIB polymorphism and risk of myocardial infarction (MI); however, the results are inconsistent. Therefore, we conducted this meta-analysis to clarify the issue based on all the data available.Eligible studies were retrieved by searching PubMed, Embase, Web of Science, and Google Scholar. We calculated the crude odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) to assess the association between the TaqIB polymorphism and risk of MI.We included 13 studies involving 8733 MI cases and 8573 controls in the meta-analysis. The pooled results from all included studies showed decreased MI risk in the analysis of the B2B2 versus B1B1 (OR = 0.78, 95% CI = 0.68-0.91), dominant (OR = 0.88, 95% CI = 0.77-0.99), and recessive genetic models (OR = 0.84, 95% CI = 0.78-0.91). The frequency of the B2B2 genotype in MI patients was lower (OR = 0.87, 95% CI = 0.81-0.94). However, there was no significant association in the B1B2 versus B1B1 analysis (OR = 0.92, 95% CI = 0.81-1.05) and no significant difference for the B1B1 genotype (OR = 1.04, 95% CI = 0.98-1.11) and B1B2 genotype (OR = 1.03, 95% CI = 0.97-1.08). Cumulative analysis confirmed these results.Our results suggest that the B2B2 genotype of the CETP TaqIB polymorphism is a protective factor against the development of MI.